TiO2 nanowired delivery of DL-3-n-butylphthalide (DL-NBP) with neprilysin induces neuroprotection in Alzheimer's disease
TiO2 nanowired DL-3-n-butylphthalide (DL-NBP) reduces brain pathology in concussive head injury (CHI). Since, neprilysin (NPL) is the rate-limiting enzyme for amyloid-beta peptide (AβP) we demonstrate that DL-NBP with NPL if delivered together has superior neuroprotective effects in AD. DL-NBP alone in high doses was also able to significantly reduce AD pathology following intraventricular (i.c.v.) administration of AβP (1-40, 250 ng/10 µl), once daily) for 4 weeks. Co-administration of TiO2 nanowired DL-NBP (40 mg/kg, i.v. once daily for 7 days) with NPL (100 µl in 50 µl, i.c.v.) once daily for 1 week after 2 weeks of AβP infusion significantly reduced brain pathology and behavioural dysfunction. Increased NPL in hippocampus (400 pg/g) with significant decrease in the AβP deposition (45 pg/g from untreated control 75 pg/g; control 40±4 pg/g) was seen with this combined treatment. Interestingly, these changes were also evident when TiO2-DL-NBP was given alone at a high dose (60 mg/kg, i.v.) for 7 days or 10 days under identical conditions. These observations are the first to show that co-administration of TiO2-nanowired DL-NBP with NPL or NBP alone could reduce AD pathology if given for longer time periods or in high doses, not reported earlier.
Neuroprotection in Brain blast injury at hot environmentt by Nanowired delivery of cerebrolysin with mesenchymal stem cells
Blast brain injury (bBI) was inflicted in a shock tube where compressed air-and helium-induced membrane rupture causing pressure waves (100, 150 or 200 kPa) with velocity of ca. 400 to 450 m/sec. The animals survived 8 or 12 h after bBI. Identical bBI was induced in rats exposed to HE at 38°C for 2 h daily for 1 week. Our innovation showed a progressive BBB breakdown in the cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus and brain stem correlating well with blast overpressure strength. Regional cerebral blood flow (rCBF) reduced by -30 to -58 % associated with edema formation with 8 to 16 % higher volume swelling. Expansion of neuropil, sponginess and neuronal, glial and myelin damages are quite frequent in bBI that were 2-to 3-fold higher after identical bBI at HE. Nanodelivery of CBL (5 ml/kg, i.v.) or MSCs (106 cells, i.v.) either 30 min or 1 h after bBI significantly reduced brain pathology in normal animals however TiO2 nanodelivery of CBL (5 ml/kg, i.v.) together with MSCs (106 cells, i.v.) is needed for neuroprotection in bBI at HE. This innovation showed that nanowired CBL and MSCs is needed for neuroprotection after bBI in HE animals.
Phospho-CSE1L Antibody-Drug Conjugates for Extensive Cancer Treatments
Typical antibody-drug conjugates (ADC) can only treat a specific cancer type. Also, as tumors are often heterogeneous, ADCs won’t be able to eradicate heterogeneous cancer cells and this renders cancer relapse. For example : kadcyla only treats Her2-positive breast tumor, recurrences are easy due to proliferation of HER2-nagative tumor cells. CSE1L (1) is highly expressed in most cancer types, (2) it exists as an microvesicle/exosome membrane protein that primarily accumulates in tumors. (3) CSE1L can be stimulated by oncogene to become phospho-CSE1L. Tumor cells often express abnormal oncogene thus have high phospho-CSE1L , while normal cells don’t express abnormal oncogene. Thus, phospho-CSE1L is a potential target for developing antibody-drug conjugates (ADC) that can specifically target tumor cells and extensive cancer treatments. Tumors release much more microvesicles/exosomes. The “CSE1L-ADC and phospho-CSE1L-ADC” featured in our patent (Claim: An anti-CSE1L carrier-conjugated antibody or an anti-phospho-CSE1L carrier-conjugated antibody for in vivo tumor targeting.) may be able to offer better therapy efficacy and enables development of ADCs cancer drugs, radiation cancer drugs, liposome cancer drugs for treating most cancer types, as well as targeted tumor contrast agents and so forth.
imple & Rapid Bacterial Detection Using Chimeric Phages
Rapidly identifying a bacterial infection in order to correctly target and kill bacteria has life-saving potential. Annually, millions of people are given the wrong antibiotic resulting in tens of thousands of deaths. This technology allows for the identification and potentially therapeutic targeting of multitudes of bacteria. The technology enables engineered-phages linked to a detection or cytotoxic platform to be designed against a vast array of bacteria. In order to generate a rapid colored result, the engineered-phages linked to gold or silver nanoparticles cause trigger the aggregation of the particles upon binding the targeted bacteria which in turn produces an easily measured visible color change. The color change is evident in 20 minutes or less making it substantially fasted that current technologies. The same approach can be applied killing bacteria if the engineered-phage is linked to a cytotoxin. This would allow for a specific and targeted antibacterial treatment. The flexibility in targeting, combined with the specificity of targeting and its speed make it unique and hugely versatile.
Superior neuroprotection in concussive head injury at hot environment by nanowired delivery of cerebrolysin with neprilysin combined with antibodies to amyloid beta peptide
CHI was inflicted by dropping a weight of 114.6 g from 20 cm height on the exposed parietal skull bone in rats either acclimatized at RT (21±1°C) or at HE (34°C for 4 h per day for 2 weeks in biological oxygen demand incubator (BOD, relative humidity 45-47 %, wind speed 20-25 cm/sec). HE alone did not result in BBB breakdown, edema formation or changes in AbP or tau levels. However, CHI in HE resulted in 250 to 285 % higher breakdown of the BBB to Evans blue albumin and radioiodine (-I) and neuronal, glial and axonal damage following identical CHI at RT after 24 trauma. The AbP and tau in CHI at HE increased by 3- to 6-fold in the CSF (control AbP 0.23±0.04; CHI-RT 0.82±0.05; CHI-HE 2.34±0.12 ng/ml); (Control tau 20±2; CHI-RT 34±6; CHI-HE 76±8 pg/ml). Nanodelivery of cerebrolysin (2.5 ml/kg, i.v.) together with 50 µl 1:20 AbP antibodies i.c.v. 4 h after CHI resulted in significant reductions in AbP levels and brain pathology in CHI at HE. Our innovation show better therapeutic avenues in treating exacerbation of brain damage following CHI at HE.
Nanowired delivery of antibodies to tau and neuronal nitric oxide synthase with cerebrolysin reduced pathophysiology of Parkinson's disease after concussive had injury
PD like symptoms was produced in mice by administering 1-metyl-4-fenyl-1,2,3,6-tetrahydropyridin (MPTP, 20 mg/kg, i.p.) daily within 2-h intervals for 5 days in normal or following concussive head injury (CHI). CHI was inflicted by an impact of 0.224 N over the right parietal bone by dropping a weight of 114.6 g from 20 cm. On the 8th day brain pathology was examined. CHI exacerbated p-tau by 1.5 to 2.3 fold in the CSF and in the right and left hemispheres in PD as compared to uninjured PD group. CHI also enhanced greater expression of nNOS, neuronal or glial cell injuries in PD as compared to the uninjured PD group. TiO2 nanowired delivery of cerebrolysin (2.5 ml/kg, i.v.) together with monoclonal p-tau antibodies (phospho S396, 1:20, 30 µl, i.c.v.) with nNOS antibodies (EP1855Y, 1.20 40 µl, i.c.v.) into the left lateral cerebral ventricle 5 days after MPTP significantly reduced blood-brain barrier (BBB) disruption and edema formation in both hemispheres after CHI in PD as compared to CBL given alone. The p-tau levels and nNOS expression were also significantly reduced in the CSF and in brain after these combined treatments in PD following CHI indicating novel therapeutic measure in PD after CHI.